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Enantioselective construction of stereogenic-at-sulfur(IV) centres via catalytic acyl transfer sulfinylation

Nature Chemistry (2024)Cite this article

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Abstract

Chiral sulfur pharmacophores are crucial for drug discovery in bioscience and medicinal chemistry. While the catalytic asymmetric synthesis of sulfoxides and sulfinate esters with stereogenic-at-sulfur(IV) centres is well developed, the synthesis of chiral sulfinamides remains challenging, which has primarily been attributed to the high nucleophilicity and competing reactions of amines. In this study, we have developed an efficient methodology for the catalytic asymmetric synthesis of chiral sulfinamides and sulfinate esters by the sulfinylation of diverse nucleophiles, including aromatic amines and alcohols, using our bifunctional chiral 4-arylpyridine N-oxides as catalysts. The remarkable results are a testament to the efficiency, versatility and broad applicability of the developed synthetic approach, serving as a valuable tool for the synthesis of sulfur pharmacophores. Mechanistic experiments and density functional theory calculations revealed that the initiation and stereocontrol of this reaction are induced by an acyl transfer catalyst. Our research provides an efficient approach for the construction of optically pure sulfur(IV) centres.

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Fig. 1: Functional chiral S(IV) groups and different strategies to construct S(IV) centres.
Fig. 2: Synthetic transformations of sulfinamides and a sulfinate ester.
Fig. 3: Experimental mechanistic studies.
Fig. 4: Catalytic mechanism.

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Data availability

The data that support the findings of this study are available within the main text and the Supplementary Information. The X-ray crystallographic coordinates for the structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers 2285509 (4o), 2285510 (6y) and 2311965 (7d). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

We are grateful to the NSFC (grant nos. 22071046, U22A20378 and 21971056) and the Program for Innovative Research Team in Science and Technology at the University of Henan Province (grant nos. 23IRTSTHN003 and 22IRTSTHN003) for financial support. We also thank the Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, the Henan Key Laboratory of Organic Functional Molecules and Drug Innovation and the NMPA Key Laboratory for Research and Evaluation of Innovative Drug for financial support.

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Authors and Affiliations

  1. School of Environment, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, China

    Tao Wei, Han-Le Wang, Ming-Sheng Xie & Hai-Ming Guo

  2. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China

    Yin Tian

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Contributions

H.-M.G., M.-S.X. and Y.T. conceived and directed the project. T.W. and H.-L.W. performed the experiments. Y.T. performed the computational studies. H.-M.G. and M.-S.X. supervised the work. M.-S.X. and T.W. co-wrote the original draft of the paper. M.-S.X., Y.T. and H.-M.G. co-wrote the final paper.

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Correspondence to Yin Tian, Ming-Sheng Xie or Hai-Ming Guo.

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Nature Chemistry thanks Choon-Hong Tan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–6 and Tables 1–10.

Supplementary Data 1

Cartesian coordinates for the theoretical calculations.

Supplementary Data 2

Crystallographic data for compound 4o; CCDC reference 2285509.

Supplementary Data 3

Crystallographic data for compound 6y; CCDC reference 2285510.

Supplementary Data 4

Structure factors for compound 6y; CCDC reference 2285510.

Supplementary Data 5

Crystallographic data for compound 7d; CCDC reference 2311965.

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Wei, T., Wang, HL., Tian, Y. et al. Enantioselective construction of stereogenic-at-sulfur(IV) centres via catalytic acyl transfer sulfinylation. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01522-z

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